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Volume 69, Issue 3 , Pages 450-462, September 2013
Volume 69, Issue 3 , Pages 450-462, September 2013
The skin and hypercoagulable states
Article Outline
- Abstract
- Hemostasis
- Hypercoagulable states
- Skin manifestations and syndromes
- The use of antiplatelet and anticoagulant therapy in dermatology
- Conclusion
- References
- Copyright
Hypercoagulable states (HS) are inherited or acquired conditions that predispose an individual to venous and/or arterial thrombosis. The dermatologist can play a vital role in diagnosing a patient's HS by recognizing the associated cutaneous manifestations, such as purpura, purpura fulminans, livedo reticularis, livedo vasculopathy (atrophie blanche), anetoderma, chronic venous ulcers, and superficial venous thrombosis. The cutaneous manifestations of HS are generally nonspecific, but identification of an abnormal finding can warrant a further workup for an underlying thrombophilic disorder. This review will focus on the basic science of hemostasis, the evaluation of HS, the skin manifestations associated with hypercoagulability, and the use of antiplatelet and anticoagulant therapy in dermatology.
Key words: anetoderma, antiphospholipid antibody syndrome, chronic venous ulcer, hemostasis, hypercoagulable states, livedo reticularis,livedo vasculopathy, purpura, superficial venous thrombosis, thrombosis
Abbreviations used: APC, activated protein C, APLA, antiphospholipid antibody, APLS, antiphospholipid antibody syndrome, CVU, chronic venous ulceration, DIC, disseminated intravascular coagulation, DVT, deep venous thrombosis, HIT, heparin-induced thrombocytopenia, HS,hypercoagulable states, LMWH, low-molecular-weight heparin, LR, livedo reticularis, LV, livedo vasculopathy, PE, pulmonary embolism, PF,purpura fulminans, SVT, superficial venous thrombosis, TF, tissue factor, TTP, thrombotic thrombocytopenic purpura, VTE, venous thromboembolism
Capsule Summary
Hemostasis
Hemostasis is the physiologic response that minimizes blood loss while maintaining blood flow after an injury to a vessel. Endothelial injury triggers immediate vasoconstriction and exposes tissue factor (TF) and collagen in the subendothelial matrix, providing a surface for platelet adherence and plug formation. Traditionally, coagulation has been described as a cascade of enzyme reactions, consisting of the extrinsic and intrinsic pathways converging on the common pathway to produce an insoluble fibrin clot.1, 2, 3 Although the extrinsic and intrinsic pathways correlate with the laboratory values of prothrombin time and partial thromboplastin time, respectively, this model has shortcomings and fails to describe the importance of cells during the coagulation process.3 Thus, a “cell-based” model of coagulation has been proposed, which consists of 3 phases: initiation, amplification, and propagation (Fig 1), and results in platelet activation and fibrin clot production.3 TF, a cell membrane glycoprotein, is responsible for the initiation of coagulation, which occurs on the surface of a TF-bearing cell and results in the production of small amounts of thrombin (activated [a] factor [F] II).3 During amplification, thrombin generated in the initiation phase activates factors V, VIII, and XI on the negatively charged phospholipid surface of a platelet leading to platelet activation.3 Finally, in the propagation phase, significant amounts of thrombin are generated on the surface of an activated platelet, resulting in the conversion of fibrinogen into insoluble fibrin.3, 4, 5
Fig 1.
Simplified cell-based model of coagulation. A, Initiation and amplification. On surface of tissue factor (TF)-bearing cell, such as fibroblast, TF complexes with activated factor VII (FVIIa) to activate FIX and FX, ultimately resulting in thrombin (FIIa) generation via FVa and FXa prothrombinase complex.3, 4 Amplification occurs on platelet, and thrombin formed during initiation phase activates FV, FVIII, and FXI, leading to activated platelet. B,Propagation. During propagation, significant amounts of thrombin are formed on surface of activated platelet via prothrombinase complex and tenase complex (FIXa and FVIIIa).5Thrombin cleaves soluble fibrinogen to insoluble fibrin, which polymerizes and is cross-linked by FXIIIa. Plasmin, activated by tissue plasminogen activator from plasminogen, is responsible for fibrinolysis.
Hypercoagulable states
Venous and arterial thromboses are major causes of morbidity and mortality. Venous thromboembolism (VTE) includes deep venous thrombosis (DVT) and pulmonary embolism (PE). Hypercoagulability, in addition to stasis (slow flow) and endothelial injury, compose the Virchow triad of risk factors for venous thrombosis.6 Several components can contribute to a thrombophilic state, including genetic and acquired risk factors (Table I), triggering factors, and/or a lack of appropriate pharmacologic or nonpharmacologic prophylaxis. Arterial thrombosis results in an ischemic event, such as acute coronary syndrome, stroke, or limb ischemia. These events are often the consequence of a ruptured atherosclerotic plaque that provides a surface for platelet aggregation that can lead to vessel occlusion.7 In these high-flow vessels, platelets are the primary mediators of thrombosis.
Table I. Primary and secondary hypercoagulable states
Hypercoagulable states (HS) can be divided into primary (inherited) or secondary (acquired) conditions (Table I) and are associated with increased risk of venous thrombosis or both venous and arterial thrombosis (Table II). The cutaneous manifestations of HS are generally not specific for a certain condition, but recognition of an abnormal finding can warrant a further workup for an underlying thrombophilic condition or VTE.
Table II. Risks factors for venous and arterial thrombosis
The evaluation of HS begins with a thorough history and physical examination. The dermatologist can recognize cutaneous findings that are associated with underlying HS and perform a skin biopsy and laboratory tests to further evaluate. The preliminary laboratory tests used to evaluate for HS are listed in Table III, and include gene mutations, antiphospholipid antibodies (APLAs), and anticoagulant activity levels. In addition to blood work, compression ultrasonography can be used to evaluate the deep venous system if a patient has a suspected DVT or superficial venous thrombosis (SVT). If there are symptoms to suggest PE, imaging studies such as a high-resolution computed tomography scan of the chest with contrast or ventilation perfusion scan may be obtained. For arterial thrombosis, Doppler studies, angiography, or magnetic resonance angiography can be performed. Appropriate referral to specialists should be considered, including the hematologist, internist, or intensivist, depending on the clinical scenario.
Table III. Laboratory tests for evaluation of hypercoagulable states
APLA, Antiphospholipid antibody; dRVVT, dilute Russell viper venom test; HS, hypercoagulable states; MTHFR, methyltetrahydrofolate reductase; PL, phospholipid; PTT, partial thromboplastin time.
Primary HS
Factor V Leiden
Factor V Leiden is the most common primary HS, occurring in 5% to 15% of the population and inherited in an autosomal dominant pattern.6 Approximately 20% of patients presenting with their initial episode of VTE have a FV Leiden mutation.8 A point mutation in the FV gene switches guanine (G) to adenine (A) at nucleotide 1691 and codes for glutamine instead of arginine. FV is usually inactivated by activated protein C (APC) by cleavage at 3 sites, however, the FV Leiden mutant is resistant to degradation by APC.9, 10 The FV Leiden mutation accounts for over 90% of APC resistance.11
Prothrombin G20210A
Prothrombin G20210A mutation is the second most common primary HS, present in approximately 5% of the population, and also inherited in an autosomal dominant pattern.11 This mutation is present in approximately 10% of patients presenting with their initial episode of VTE.8 A mutation at nucleotide 20210 in the 3'-untranslated region of the prothrombin gene causes a guanine (G) to adenine (A) substitution.12 This mutation is associated with elevated plasma levels of prothrombin and increased thrombin formation.13
Methyltetrahydrofolate reductase and hyperhomocysteinemia
Homocysteine is an amino acid, with elevated serum levels leading to increased risk of both venous and arterial thrombosis through an unknown mechanism. Inherited causes are secondary to mutation of the enzyme methyltetrahydrofolate reductase, or less commonly cystathione-β-synthase; the enzyme deficiency in congenital homocystinuria.11 Patients with a homozygous methyltetrahydrofolate reductase mutation are at increased risk of VTE.14 Acquired hyperhomocysteinemia can be secondary to renal or thyroid disease, smoking, aging, or a vitamin deficiency (B12, B6, or folate).
Antithrombin III
Antithrombin III deficiency was the first primary thrombophilic state identified, inherited in an autosomal dominant pattern and occurring in less than 0.02% of the population.11, 15 Antithrombin III degrades thrombin (IIa) and multiple other activated coagulation factors (IXa, FXa, XIa, and XIIa), thus a deficiency leads to a thrombophilic state because of increased levels of these activated factors. The heterozygous deficiency can be quantitative (type I) or qualitative (type II). The homozygous condition is usually fatal in the neonatal period. Antithrombin III deficiency, and protein C and S deficiency, can be acquired secondary to consumption (infection, sepsis, disseminated intravascular coagulation [DIC]), decreased production (hepatic failure), or excess loss (nephrotic syndrome).
Protein C or protein S deficiency
Heterozygous protein C deficiency is an autosomal dominant condition present in 0.2% of the population and heterozygous protein S deficiency is an autosomal dominant condition present in less than 0.1% of the population.11 Homozygous protein C or protein S deficiency often results in neonatal purpura fulminans (PF) and is usually fatal.16 There have been numerous mutations of the protein C gene identified. The deficiency can either be quantitative (type I) or qualitative (type II). APC, in conjunction with its cofactor, protein S, inactivates FVa and FVIIIa, thus protein C or protein S deficiency leads to unbalanced activation of these factors and increased production of thrombin.9 Protein C or protein S deficiency can also be acquired secondary to consumption, decreased production, or excess loss, by similar mechanisms as acquired antithrombin III deficiency.
Secondary HS
Hospitalization, trauma, and surgery
Hospitalization is a risk factor for VTE, likely as a result of immobilization, with the severity of the illness also contributing to the risk.17 Patients admitted with major trauma are at an exceptionally high risk of DVT. A prospective study of 349 patients with major trauma identified at least 1 DVT present in 58% of the patients.18 Patients undergoing surgical procedures are also at increased risk of VTE, with numerous associated risk factors, including patient age, a history of VTE, the type and duration of the surgery, and comorbid conditions.
Obesity
The cause of venous and arterial hypercoagulability in obese patients is multifactorial.19, 20 Increased levels of fibrinogen, FVII, FVIII, von Willebrand factor, and plasminogen activator inhibitor have been described, however the exact mechanisms predisposing to thrombosis are unclear.19 The body mass index (kg/m2) correlates with risk of VTE, and increased fat deposition around the abdomen and upper body is associated with arterial thrombosis.21 In addition, elevated levels of leptin, a hormone produced by adipocytes, has been shown to increase the risk of arterial thrombosis.22
Cancer
Patients with cancer are at a higher risk of VTE and arterial thrombosis, with venous thrombosis as the second leading cause of mortality.23 Venous or arterial thrombosis occurs in 15% to 20% of patients with cancer.24 The risk of thrombosis is related to the actual disease and to the associated treatments and procedures. Elevated levels of fibrinogen, FV, FVIII, FIX, FX, fibrin degradation products, and platelets have been reported with malignancy.25 In addition, TF is expressed at higher levels on the surfaces of tumor cells.26 Surgery, chemotherapy, indwelling catheters, immobilization, and infections are other common risk factors leading to an increased risk of thrombosis in patients with cancer.27, 28 The most common malignancies associated with thrombosis include pancreas, stomach, uterus, kidney, lung, and primary brain tumors.29Stomach and pancreas cancer are at very high risk for chemotherapy-associated VTE.29
Medications
Medications can be associated with HS. Hormonal medications, including oral contraceptive pills, estrogen replacement therapy, and selective estrogen receptor modulations are associated with increased risk of thrombosis. Chemotherapeutic agents, including bevacizumab, thalidomide, lenalidomide, cyclophosphamide, chlorambucil, and nitrogen mustard contribute to hypercoagulability in patients with cancer. Commonly used anticoagulants, including heparin and warfarin, can paradoxically be associated with thrombosis, as discussed later.
Pregnancy
Women are at an increased risk of VTE during pregnancy and the postpartum period, with VTE occurring in 0.5 to 2.2 of 1000 pregnancies.30, 31 Women are at the highest risk of DVT during the third trimester, whereas the risk of PE is highest during the postpartum period.31 There are several mechanisms contributing to hypercoagulability in pregnancy, including venous stasis, alterations in coagulation factors, and damage to the venous system.32 During pregnancy, there is increased production of thrombin33 and increased levels of factors VII, VIII, and X; fibrinogen; and von Willebrand factor.32 In addition, there are decreased levels of protein S and resistance to APC.31 Pregnant women should be assessed for thrombophilic risk factors, especially a history of VTE, with low-molecular-weight heparin (LMWH) as the treatment of choice if prophylaxis or treatment of VTE if indicated.32
Skin manifestations and syndromes
Purpura and associated conditions
Purpura
Purpura consists of 5- to 20-mm nonblanching erythematous to violaceous macules, often located on the lower extremities. Many HS produce noninflammatory purpura with microvascular occlusion (Fig 2, A) and the associated conditions include: PF, thrombotic thrombocytopenic purpura (TTP), warfarin (Coumadin) necrosis, heparin-induced thrombotic thrombocytopenia, calciphylaxis, and catastrophic APLA syndrome (APLS).
Fig 2.
Purpura fulminans (PF). A, Noninflammatory microvascular occlusion. B, PF manifesting as purpura and hemorrhagic bullae from Escherichia coli sepsis. (A, Hematoxylin-eosin stain; original magnification: ×10.)
PF (Fig 2) is a dermatologic emergency and presents as multiple violaceous, nonblanching retiform macules and skin necrosis. Cutaneous findings can also include hemorrhagic bullae. Noninfectious neonatal PF occurs secondary to a congenital homozygous deficiency of protein C or S.16 The most common infectious cause of PF is meningococcemia and 15% to 25% of patients with this infection develop PF.34 Neonatal PF has also been reported with group B streptococcus infection.34 Acquired PF is secondary to DIC, sepsis, trauma, malignancy, obstetric complications, hepatic failure, or toxic or immunologic reactions.35 In DIC, the consumption of clotting factors and platelets leads to both thrombosis and hemorrhage. The laboratory abnormalities of DIC include prolonged prothrombin time and partial thromboplastin time, thrombocytopenia, decreased fibrinogen, and increased fibrin split products, including D-dimer. The treatment of DIC involves treating the underlying cause, and cautious use of anticoagulants and blood products.
Thrombotic thrombocytopenic purpura
TTP can be congenital, acquired, or idiopathic, and is classically described by the pentad of fever, hemolytic anemia, thrombocytopenia, renal failure, and neurologic symptoms. The pathogenesis for the majority of patients with acquired TTP involves deficiency of ADAMTS13, a metalloprotease responsible for cleaving polymers of von Willebrand factor during thrombus formation.36, 37 Decreased levels of this enzyme lead to platelet accumulation and microthrombi. The congenital form is a result of a deficiency of ADAMTS13 whereas the acquired form is a result of an IgG antibody to ADAMTS13. Idiopathic TTP cannot be explained by ADAMS13 deficiency and the cause remains unknown. The diagnosis of TTP is based on the characteristic clinical findings. Cases of suspected acquired TTP may be confirmed by the presence of anti-ADAMTS13 antibodies. The most common treatments for TTP include plasmapheresis and rituximab.37
Warfarin necrosis
Warfarin (Coumadin) necrosis can occur in patients with heterozygous protein C or S deficiency after starting the anticoagulant warfarin.11 Warfarin, a vitamin-K antagonist, is used for anticoagulation via inhibition of the vitamin K–dependent coagulation factors, which include FII, FVII, FIX, and FX, as well as proteins C and S. Within 3 to 5 days of initiating warfarin, patients with protein C or S deficiency are at risk for developing warfarin necrosis because of a temporary HS caused by the inhibition of protein C and S. Treatment starts with discontinuing warfarin and reversing its effects with vitamin K and/or fresh frozen plasma.38 Heparin is often used for anticoagulation after the warfarin is stopped, and this condition can be prevented by starting heparin before starting warfarin treatment.38 Local wound care, debridement of ulcers, mastectomy, and amputation may be necessary depending on the severity of the skin necrosis.38
Heparin-induced thrombotic thrombocytopenia
Heparin induced thrombocytopenia (HIT) is caused by the formation of antibodies to the complex of platelet factor 4 and heparin.39 HIT usually occurs 5 to 14 days after initiating heparin and is characterized by a decrease in platelets to less than 150,000, a 30% to 50% decrease in platelets from baseline, or any evidence of thrombosis.40 Symptomatic HIT occurs in 1% to 5% of patients receiving unfractionated heparin, LMWH, or fondaparinux.41, 42 Of patients with HIT, 30% develop thrombosis, also known as heparin-induced thrombotic thrombocytopenia, which has a mortality of 30% and is complicated by loss of limb in 20% of patients.40 These patients are 4 times more likely to form venous thrombosis than arterial thrombosis.40 The treatment involves discontinuing all heparin products and using an alternative anticoagulation therapy, such as a direct thrombin inhibitor, followed by a transition to long-term anticoagulation with a vitamin-K antagonist (warfarin).40
Calciphylaxis
Calciphylaxis, also known as calcific uremic arteriolopathy, is characterized by purpura, skin necrosis, nonhealing ulcers, and calcification of blood vessels. Calciphylaxis primarily affects patients with end-stage renal disease on dialysis but can also occur in nonuremic patients. This condition is associated with mortality as high as 80% when lesions are ulcerated.43The pathogenesis of this disorder is poorly understood, although it has been associated with HS, including protein C or S deficiency44, 45, 46, 47, 48 and APLS.49 In a review of reports of protein C and protein S levels and calciphylaxis, protein C was decreased in 38% of patients and protein S was decreased in 43% of patients.44 A review of 36 patients with nonuremic calciphylaxis revealed protein C or S deficiency in 11% of the patients.50 These deficiencies occurred in the setting of hepatorenal syndrome,51 alcoholic cirrhosis,52 chemotherapy,53 and rheumatoid arthritis.54 Additional evidence for the association with HS has been shown by the use of LMWH46, 55 and tissue plasminogen activator56 for the treatment of calciphylaxis, although the treatment remains controversial.
APLS and associated cutaneous findings
Antiphospholipid antibody syndrome
An APLA is an acquired antibody against cell membrane phospholipids. The most common APLAs include the lupus anticoagulant, anticardiolipin antibody, and anti-β2-glycoprotein I antibody. There are several proposed mechanisms of thrombogenesis associated with APLAs, including the inhibition of the activation of protein C and fibrinolysis, induction of TF, and activation of platelets.57 The APLA must be detected on 2 occasions (at least 12 weeks apart) to diagnose the presence of an APLA.58
APLS is diagnosed by the presence of an APLA, and a thrombotic event, such as VTE or miscarriage.58 Primary APLS occurs without an underlying medical condition whereas secondary APLS is associated with underlying autoimmune conditions, infection, malignancy, or medications. The syndrome can be associated with heart valve vegetations, thrombocytopenia, nephropathy, and neurologic complications, including transient ischemic attack and stroke. The reported skin findings associated with this condition include anetoderma (Fig 3, A), livedo reticularis (LR) (Fig 3, B), chronic venous ulcers, pseudovasculitis (Fig 3, C), superficial thrombophlebitis, superficial skin bullae (Fig 3, D), infarcts and distal gangrene, acrocyanosis, and relapsing polychondritis.
Fig 3.
Antiphospholipid antibody syndrome. A, Anetoderma. B, Livedo reticularis. C, Chronic leg ulcer and pseudovasculitic lesions. D, Superficial skin bullae.
Catastrophic APLS (Fig 4) is an accelerated form of the disease that affects the small vessels of multiple organs via acute thrombotic microangiopathy. Less than 1% of patients with APLS develop catastrophic APLS.59 Diagnosis is made by the presence of an APLA, evidence of 3 or more affected organs or systems within 1 week of onset of the disease, and demonstration of histologic vessel occlusion of at least 1 organ.59 The differential diagnosis includes DIC, however, in catastrophic APLS, the D-dimer is negative and there is a positive APLA. The treatment options include unfractionated heparin, high-dose steroids, intravenous immunoglobulin, or plasmapheresis.
Fig 4.
Catastrophic antiphospholipid antibody (APLA) syndrome. A, Auricular and facial purpura in critically ill patient with negative disseminated intravascular coagulation workup and positive APLAs. B, Right shoulder purpura in same patient.
Anetoderma, also called macular atrophy, is an elastolytic disorder of unknown origin characterized by localized areas of flaccid skin, which can appear atrophic (Fig 3, A) or protuberant. Histopathology shows a loss of dermal elastic fibers with an elastin stain, such as the Verhoeff-van Gieson stain. Primary anetoderma occurs in areas of skin with no prior skin pathology, whereas secondary anetoderma occurs in areas of skin with prior pathology, most commonly acne or varicella.60Primary anetoderma has been reported in association with HIV, penicillamine use, and autoimmune diseases including lupus and thyroiditis.61, 62, 63 Primary anetoderma has been reported as a specific skin manifestation for the underlying presence of an APLA.60, 62, 63, 64, 65, 66, 67, 68, 69 A study of 9 patients with primary anetoderma revealed APLAs in all 9 patients, with 4 patients also having APLS.70 A case report of anetoderma and chronic lower leg ulceration has been reported in association with decreased antithrombin III levels.71
Livedo reticularis
LR (Fig 3, B) is a blanching erythematous to violaceous netlike vascular pattern on the skin. Livedo racemosa is atypical LR that has prominent asymmetry and breaks in the netlike pattern. LR can be a normal physiologic finding that resolves with warming, or it can be indicative of an underlying HS. The 3 subtypes of LR not associated with systemic disease include: physiologic (cutis marmorata), primary, and idiopathic.72 A review72 of secondary LR describes the numerous associated conditions, including the following HS: APLAs,73, 74, 75 APLS,76 protein C and S deficiency, antithrombin III deficiency, DVT, DIC, and TTP. Other systemic associations include systemic vasculitis, connective tissue disease, emboli, vessel wall deposition, medications, infections, malignancy, neurologic disease, and endocrine and nutritional diseases.72
Livedo vasculopathy
Livedo vasculopathy (LV), also known as livedoid vasculopathy, atrophie blanche, segmental hyalinizing vasculitis, PURPLE (painful purpuric ulcers with reticular pattern of the lower extremities), and LR with winter or summer ulceration, is a chronic, painful, recurrent, and progressive skin disease often occurring on the lower extremities (Fig 5).77 The lesions are varied, and may consist of focal purpura with shallow ulcerations that heal leaving atrophic, stellate, scarlike white plaques stippled with telangiectasis and peripheral hyperpigmentation.78 There are many proposed mechanisms of pathogenesis of LV, including venous flow abnormalities, vascular endothelial dysfunction, immune complex deposition, and microthrombi of the dermal vessels secondary to HS.79 The reported associated HS include FV Leiden mutation,80, 81, 82 prothrombin gene mutation,83, 84 antithrombin III deficiency,85 protein C deficiency,86, 87 double heterozygous FV Leiden and prothrombin mutations,88 APLAs,89, 90 APLS,91 and hyperhomocysteinemia.92, 93, 94
Fig 5.
Atrophie blanche from livedo vasculopathy.
Chronic venous ulceration (CVU) often occurs in the setting of chronic venous insufficiency, varicose veins, or both. A prior DVT is a major risk factor for chronic venous insufficiency. Studies have shown that patients with CVU and varicose veins have increased rates of primary HS or the presence of an APLA.95 In a study of 110 patients with CVU, approximately one third of patients had an underlying primary HS, compared with 1.8% of the control patients.95 Another study of 97 patients with CVU showed 41% of patients with a thrombophilic state.96
Superficial venous thrombosis
SVT, or superficial thrombophlebitis, presents as a swollen, red, tender, cordlike area of inflammation along a superficial vein, most commonly in the lower extremities. This was once considered a benign condition however it has recently been proven to be associated with VTE in 20% to 30% of patients.97, 98 An anatomic communication between the superficial and deep venous systems exists, which presents the potential for the development of DVT by direct extension of the clot into the deeper vasculature. In the POST study, 25% of 844 patients with SVT also had DVT, PE, or both.98 In the OPTIMEV study, 29% of 788 patients had DVT.99 Varicose veins are present in 60% to 90% of patients before developing SVT.100, 101 The most commonly affected vein is the great saphenous vein, which accounts for 60% to 80% of SVT.101 This condition is more common in women with an average age of onset at 60 years.101 When SVT is associated with varicose veins, it is less likely to be complicated by extension into the deep venous system.102 Superficial thrombophlebitis has been found in association with anticardiolipin antibodies, protein C or S deficiency, FV Leiden mutation, prothrombin mutation, and antithrombin III deficiency.103, 104, 105, 106, 107 One study showed FV Leiden mutation was present in 14.3% of patients presenting with superficial thrombophebitis.106
The use of antiplatelet and anticoagulant therapy in dermatology
The pharmacologic treatments available for VTE include antiplatelet and anticoagulant medications (Table IV) and thrombolytic agents. Embolectomy may be performed to remove large thromboses and inferior vena cava filters can be placed to help prevent additional pulmonary emboli.
Table IV. Antiplatelet and anticoagulant therapies
Aspirin
LMWH, Low-molecular-weight heparin.
In dermatology, the most frequently reported use of antiplatelet and anticoagulant medication is for the treatment of LV. There have been reports of the use of unfractionated heparin or LMWH, such as enoxaparin92, 108, 109 or dalteparin.109 Other reported treatments of LV include warfarin, aspirin, dipyridamole, clopidogrel, ticlopidine, recombinant tissue plasminogen activator, and rivaroxaban.79, 110 In a case report of LV associated with a positive lupus anticoagulant and methyltetrahydrofolate reductase mutation, the patient achieved complete remission after treatment with tinzaparin (LMWH) for 6 months.111 The use of warfarin has been reported in patients with LV and FV Leiden mutation,109, 112, 113 prothrombin mutation,84 and hyperhomocysteinemia.77 Recently, the oral factor Xa inhibitor rivaroxaban was shown to decrease pain and ulceration in 3 patients with LV.110
In patients with CVU, there have been case reports of the successful use of warfarin, LMWH (enoxaparin or dalteparin), clopidogrel, and aspirin. One case of anetoderma and chronic ulceration of the lower leg associated with antithrombin III deficiency demonstrated resolution of ulceration with enoxaparin followed by fondaparinux.71
The treatment of APLS with anticoagulation has been shown to decrease recurrent thrombosis, however when the anticoagulation is stopped, the patient is at an increased risk of thrombosis during the first 6 months after discontinuation of therapy.114 If APLS is suspected, referral to a hematologist for anticoagulation recommendations is preferred for long-term management.
In patients with an SVT of at least 5 cm in length, recommended treatment includes a prophylactic dose of fondaparinux (2.5 mg subcutaneously daily).115 In the CALISTO study of 3002 patients with SVT, fondaparinux was superior to placebo in the prevention of VTE.115 Various doses and durations of LMWH have been reported with SVT. A recent randomized, double-blind study of parnaparin determined that an intermediate dose of parnaparin for 30 days was effective treatment for at least 4-cm-long SVT.116 Nonsteroidal anti-inflammatory medications have been the mainstay of treatment, and although these medications reduce the pain and recurrence of SVT, they do not decrease the incidence of VTE.117 In a patient with a first episode of DVT of the leg, the recommended treatment is warfarin for 3 months.118
Conclusion
Primary and secondary HS are associated with cutaneous manifestations, including purpura, PF, LR, LV (atrophie blanche), anetoderma, SVT, and chronic venous ulcers. The dermatologist can identify these abnormal findings and pursue a workup for an underlying HS. The successful use of numerous antiplatelet and anticoagulant medications have been reported in patients with HS and skin manifestations, however, prospective studies are still needed to determine the optimal treatment for many of these conditions.
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